Cancer claims over six million lives each year worldwide and is the largest single cause of death in both men and women. Extrinsic factors, including personal lifestyles, play a major role in the development of most human malignancies. Cigarette smoking, consumption of alcohol, exposure to synthetic and naturally occurring carcinogens, radiation, drugs, infectious agents, and reproductive and behavioral practices are widely recognized as important contributors to the etiology of cancer.
A surprising conclusion is that the human diet plays a causative role in more than one-third of human neoplasia. However, the human diet not only contains numerous mutagens and carcinogens, but also contains a variety of chemicals that block carcinogenesis in animal models. Chemoprevention, i.e., the prevention of cancer by ingestion of chemical agents that reduce the risk of carcinogenesis, therefore, is one of the most direct ways to reduce cancer-related morbidity and mortality. See, M. B. Sporn, Fed. Proc., 38, 2528 (1979).
Dietary modifications can modulate cancer risk in various ways. For example, changes in caloric intake, altering the consumption of nutritive and nonnutritive diet components, and providing exposure to numerous minor chemicals that may be genotoxic or protective can increase or decrease the risk of cancer. Modifying the human diet to reduce the risk of cancer requires the identification of dietary carcinogens and chemopreventatives, even though interactions between the factors that modulate cancer risk are complex. Whereas extensive efforts have been made to identify dietary carcinogens and mutagens, the identification of chemopreventative agents has received less attention.
Cancer chemopreventive agents include nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin, aspirin, piroxicam, and sulindac, all of which inhibit cyclooxygenase, abbreviated hereafter as COX. A COX inhibitory activity is important in cancer chemoprevention because COX catalyzes the conversion of arachidonic acid to proinflammatory substances, such as prostaglandins, which can stimulate tumor cell growth and suppress immune surveillance. O. J. Plescia et al., Proc. Natl. Acad. Sci. U.S.A., 72, 1848 (1975), and J. S. Goodwin, Am. J. Med., 77, 7 (1984). In addition, COX can activate carcinogens to forms that damage genetic material. T. V. Zenser et al., J. Pharmacol. Exp. Ther., 227, 545 (1983), and D. Wild et al., Carcinogenesis, 8, 541 (1987).
There is a need in the art, therefore, for the identification of specific compounds that have a cancer chemopreventative effect on mammals. Such cancer chemopreventative compounds then can be used in drug compositions or as food additives to reduce the risk of cancer.
Investigators have searched for new cancer chemopreventative agents by evaluating hundreds of plant extracts for a potential to inhibit COX. An extract derived from Cassia quinquangulata Rich. (Leguminosae) was identified as a potent COX inhibitor, and on the basis of bioassay-guided fractionation, resveratrol (i.e., 3,5,4'-trihydroxy--transstilbene) was identified as the active compound. See, E. Mannila et al., Phytochemistry, 33, 813 (1993), and G. S. Jayatilake et al., J. Nat. Prod. 56, 1805 (1993).